PROJECT SUMMARY The prevalence of type 2 diabetes (T2D) is increasing in youth with current management strategies ineffective at maintaining durability of glycemic control. Metformin is the cornerstone of treatment of T2D in youth, yet youth with T2D have high treatment failure rates on metformin therapy. The reasons for treatment failure remain unknown, and need to be comprehensively understood in order to optimize dosing strategies for this safe and cost-effective therapy. To address this unmet medical need, Shylaja Srinivasan MD proposes to build on her successful patient-oriented genetic research through this career development award with the overall objective to use an integrated approach to understand the determinants of metformin response in youth with T2D. With the assistance of a multi-disciplinary mentoring team, she will evaluate the pharmacological, clinical and physiological determinants of metformin response in youth with T2D. Dr. Srinivasan proposes the following aims: (1) develop a population PK model to describe the pharmacokinetics (PK) of metformin in youth with T2D; (2) characterize the variance in long-term response to metformin, integrating comprehensive clinical, pharmacological and genetic data with disease progression in youth with T2D and develop a clinically usable precision dosing tool; and (3) evaluate the precision dosing tool for metformin in a pilot study of youth with T2D in a real clinical setting. To advance these studies, she has access to large datasets and samples from pediatric patients with T2D. In Aim 1, Dr. Srinivasan will develop a population PK model using PK data from 60 youth with T2D recruited from UCSF. In Aim 2, she will develop a longitudinal model to characterize the association between dose, predicted metformin PK (Aim 1), clinical factors, genetic factors if any and metformin response using samples already collected from 699 youth with T2D from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. She will then utilize these results to develop a clinically usable precision dosing tool. In Aim 3, she will evaluate the precision dosing tool in a pilot study of 20 youth from UCSF, comparing precision dosing with conventional dosing for metformin in a real clinical setting. Results from this proposal will inform an R01 in which precision dosing algorithms for metformin will be tested in a large randomized control trial and will be expanded to include other drug classes. Dr. Srinivasan's long- term career goal is to become an independent clinical researcher and to leverage pharmacological and genetic methods to improve therapeutic strategies for youth with T2D. In this career development award, her training goals are to gain experience in clinical pharmacology and quantitative pharmacokinetics; become proficient in advanced biostatistical methods; gain experience in the conduct of pediatric clinical trials; and engage in career development activities in preparation for R01 funding. She will accomplish these goals with the advice and mentoring from a world-class multi-disciplinary mentoring team, participation in relevant didactic coursework and hands-on research experience, all necessary for future independent research success.